Clofarabine with high dose cytarabine and granulocyte colony‐stimulating factor (G‐CSF) priming for relapsed and refractory acute myeloid leukaemia

Abstract

SUMMARY This phase I/II study was conducted to determine the maximum tolerated dose, toxicity, and efficacy of clofarabine in combination with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming (GCLAC), in the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML). Dose escalation of clofarabine occurred without dose-limiting toxicity, so most patients were treated at the maximum dose, 25 mg/m2/day with cytarabine 2 g/m2/day, each for 5 days, and G-CSF 5 μg/kg, beginning the day before chemotherapy and continuing daily until neutrophil recovery. The complete remission (CR) rate among the 46 evaluable patients was 46% (95% confidence interval [CI] 31–61%) and the CR + CR but with a platelet count <100 x 109/l rate was 61% (95% CI 45–75%). Multivariate analysis showed that responses to GCLAC were independent of age, cytogenetic risk category, and number of prior salvage regimens. GCLAC is highly active in relapsed and refractory AML and warrants prospective comparison to other regimens, as well as study in untreated patients.

Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes

“…Investigators have examined clofarabine's role in relapsed or refractory AML in multiple phase I-II studies and a single randomized controlled trial [6]. The ranges for overall response and complete response rates assessing the combination of clofarabine with cytarabine are 40-61% and 24-46%, respectively [5,[7][8][9][10][11][12]. The largest trial of clofarabine to date in the relapsed/refractory setting, CLASSIC I, was the only randomized controlled trial of this agent in the AML setting: in CLASSIC I, the combination of clofarabine and cytarabine was associated with overall and complete response rates of 47% and 35%, respectively, compared to 22% and 18% with cytarabine monotherapy.…”

Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia

“…Overall CR rates with intensive regimens generally range from about 30% to about 65%, and median OS is generally around 8-9 months (see Table 2) [51,57,[60][61][62][63][64]. Rates of early death (e.g., induction deaths, aplastic deaths or 30-day mortality) in these studies were generally between about 5% and 15% [51,57,[60][61][62][63][64]. A combination of mitoxantrone and etoposide is another option, which is associated with similar CR rates and OS around 6 months [58,59].…”

Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy

“…[3][4][5] According to current practice and National Comprehensive Cancer Network (NCCN) guidelines, allogeneic hematopoietic cell transplantation (HCT) should be offered to patients who achieve CR but are at high risk for relapse, based on various genetic, molecular or clinical risk factors. 6,7 Patients, who relapse after initial remission, in general, may achieve a second CR in 30-45% of the time when using a more aggressive reinduction regimen [8][9][10][11][12][13][14] ; this rate can be as low as 10-15% in patients whose first CR lasted for o1 year. 15 Patients with primary induction or reinduction failure have poor prognosis with minimal, if any chance of cure using alternative chemotherapy or early-phase clinical trials testing investigational agents.…”